Mucoadhesive in situ forming Gels: Bridging Formulation design and physiological Realities

Abstract

Thermosensitive mucoadhesive in situ forming gels are sprayable liquids at room temperature, that form hydrogels which can adhere to the mucosal tissue at body temperature. These versatile drug delivery systems can be effectively utilized as localized drug delivery vehicles in the oral cavity. However, conventional methods to assess these products often overlook the influence of physiological factors (such as the presence of saliva and gravitational effects), all of which can potentially result in misleading conclusions about formulation performance. The main objective of the present research is to evaluate the impact of physiological factors on key performance markers (such as gelation temperature, mucoadhesion, rheology, and drug release) of in situ forming oral gels comprising different mucoadhesive polymers. A comprehensive comparison was conducted between traditional evaluation methods and methods that incorporate physiological factors. The physiologically relevant methods demonstrated higher gelation temperatures and reduced mucoadhesion, highlighting the importance of physiological relevance in formulation screening. Small Angle X-ray Spectroscopy (SAXS) and rheological oscillatory temperature sweeps revealed the formation of a hexagonal liquid crystalline micellar arrangement at physiological temperature (35 °C), leading to a sustained in vitro drug release over 4-6 h. Moreover, drug release was shown to be significantly influenced by the presence of salivary amylase, the pH of the release medium, and the chemistry and solubility of the mucoadhesive polymers. Notably, formulations containing chitosan exhibited faster drug release rates at lower pH, attributed to the increased solubility of chitosan in acidic conditions. In contrast, formulation containing sodium alginate demonstrated slower release rates due to ionic crosslinking with components in the artificial saliva, which reduced polymer dissolution and drug diffusion. The current research emphasizes the importance of integrating physiological factors in early-stage formulation evaluation to enable accurate performance prediction, ensuring that suboptimal candidates are identified before advancing to clinical studies. The novel insights obtained can serve to guide formulation design and evaluation approaches for other oral mucoadhesive systems.

Keywords: Gelation temperature; In situ forming hydrogels; In vitro release; Liquid crystal structure; Mucoadhesive drug delivery; Rheology; Salivary flow.